抑制CYP3A4-mediated新陈代谢和P-glycoprotein-mediated运输的hiv - 1蛋白酶抑制剂saquinavir葡萄柚汁组件。
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鹰VA、利润L, DJ
抑制CYP3A4-mediated新陈代谢和P-glycoprotein-mediated运输的hiv - 1蛋白酶抑制剂saquinavir葡萄柚汁组件。
Br中国新药杂志。1999年10月,48 (4):543 - 52。
- PubMed ID
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10583025 (在PubMed]
- 文摘
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目的:细胞色素P450 3 a4 (CYP3A4)和22 (P-gp)都表示在肠粘膜和口腔给药的障碍。CYP3A4和P-gp共享重叠的组织分布和底物特异性。葡萄柚汁与CYP3A4基质相互作用是有据可查的,发生由于肠道CYP3A4的监管。本研究的目的是对CYP3A4-mediated屏幕葡萄柚汁组件新陈代谢和hiv - 1蛋白酶抑制剂saquinavir P-gp介导运输。方法:五个葡萄柚汁组件:槲皮素、柚皮苷,柚苷配基,6 ',7 ' -dihydroxybergamottin bergamottin筛选的潜在抑制剂的新陈代谢saquinavir由人类肝脏微粒体。已知的CYP3A4抑制剂酮康唑也抑制潜在的筛查。这些化合物也筛选调节器P-gp活动通过评估saquinavir的定向运输Caco-2单层细胞表达P-gp。维拉帕米的影响,一个已知的调制器P-gp函数,也决定在这些细胞系。结果:在预孵化,6 ',7 ' -dihydroxybergamottin bergamottin抑制saquinavir的新陈代谢,妈妈IC50值为0.33 + / - -0.23和0.74 + / - -0.13妈妈,分别为(n = 3)。酮康唑达到0的IC50。 55+/-0.12 muM (n=4). The other compounds studied failed to reach IC50 at concentrations of up to 100 muM. The transport of saquinavir in the basolateral-->apical (BL-->AP) direction exceeded that in the apical -->basolateral direction (AP-->BL), with apparent permeability coefficients of 199.2+/-15.8x10-7 cm s-1 and 8.00+/-1. 13x10-7 cm s-1, respectively (n=3) which is indicative of a polarized efflux mechanism. The ratio of BL-->AP/AP-->BL for saquinavir was 25, but in the presence of verapamil and ketoconazole this ratio was reduced to 3.6 and 4.0, respectively (n=3), indicating extensive inhibition of P-gp mediated saquinavir efflux. Of the grapefruit juice components studied only naringin and 6', 7'-dihydroxybergamottin had any appreciable effect, reducing the ratio to 7.6 and 7.1, respectively (n=3); but this was due solely to increased AP-->BL transport. CONCLUSIONS: Grapefruit juice components inhibit CYP3A4-mediated saquinavir metabolism and also modulate, to a limited extent, P-gp mediated saquinavir transport in Caco-2 cell monolayers. The in vivo effects of grapefruit juice coadministration are most likely the result of effects on CYP3A4 (inhibition and down regulation) and only to a minor extent on modulation of P-gp function.